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A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma

(2010) CLINICAL CANCER RESEARCH. 16(16). p.4278-4288
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Abstract
Purpose: Hepatocellular carcinomas (HCC) have an unpredictable clinical course, and molecular classification could provide better insights into prognosis and patient-directed therapy. We hypothesized that in HCC, certain microenvironmental regions exist with a characteristic gene expression related to chronic hypoxia which would induce aggressive behavior. Experimental Design: We determined the gene expression pattern for human HepG2 liver cells under chronic hypoxia by microarray analysis. Differentially expressed genes were selected and their clinical values were assessed. In our hypothesis-driven analysis, we included available independent microarray studies of patients with HCC in one single analysis. Three microarray studies encompassing 272 patients were used as training sets to determine a minimal prognostic gene set, and one recent study of 91 patients was used for validation. Results: Using computational methods, we identified seven genes (out of 3,592 differentially expressed under chronic hypoxia) that showed correlation with poor prognostic indicators in all three training sets (65/139/73 patients) and this was validated in a fourth data set (91 patients). Retrospectively, the seven-gene set was associated with poor survival (hazard ratio, 1.39; P = 0.007) and early recurrence (hazard ratio, 2.92; P = 0.007) in 135 patients. Moreover, using a hypoxia score based on this seven-gene set, we found that patients with a score of > 0.35 (n = 42) had a median survival of 307 days, whereas patients with a score of = 0.35 (n = 93) had a median survival of 1,602 days (P = 0.005). Conclusions: We identified a unique, liver-specific, seven-gene signature associated with chronic hypoxia that correlates with poor prognosis in HCCs.
Keywords
INTRAHEPATIC RECURRENCE, GENE-EXPRESSION SIGNATURE, THERAPEUTIC TARGETS, COLORECTAL-CANCER, BREAST-CANCER, CLASSIFICATION, CELLS, PREDICTION, SURVIVAL, TUMORS

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Chicago
van Malenstein, Hannah, Olivier Gevaert, Louis Libbrecht, Anneleen Daemen, Joke Allemeersch, Frederik Nevens, Erik Van Cutsem, et al. 2010. “A Seven-gene Set Associated with Chronic Hypoxia of Prognostic Importance in Hepatocellular Carcinoma.” Clinical Cancer Research 16 (16): 4278–4288.
APA
van Malenstein, H., Gevaert, O., Libbrecht, L., Daemen, A., Allemeersch, J., Nevens, F., Van Cutsem, E., et al. (2010). A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma. CLINICAL CANCER RESEARCH, 16(16), 4278–4288.
Vancouver
1.
van Malenstein H, Gevaert O, Libbrecht L, Daemen A, Allemeersch J, Nevens F, et al. A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma. CLINICAL CANCER RESEARCH. 2010;16(16):4278–88.
MLA
van Malenstein, Hannah, Olivier Gevaert, Louis Libbrecht, et al. “A Seven-gene Set Associated with Chronic Hypoxia of Prognostic Importance in Hepatocellular Carcinoma.” CLINICAL CANCER RESEARCH 16.16 (2010): 4278–4288. Print.
@article{3086719,
  abstract     = {Purpose: Hepatocellular carcinomas (HCC) have an unpredictable clinical course, and molecular classification could provide better insights into prognosis and patient-directed therapy. We hypothesized that in HCC, certain microenvironmental regions exist with a characteristic gene expression related to chronic hypoxia which would induce aggressive behavior. 
Experimental Design: We determined the gene expression pattern for human HepG2 liver cells under chronic hypoxia by microarray analysis. Differentially expressed genes were selected and their clinical values were assessed. In our hypothesis-driven analysis, we included available independent microarray studies of patients with HCC in one single analysis. Three microarray studies encompassing 272 patients were used as training sets to determine a minimal prognostic gene set, and one recent study of 91 patients was used for validation. 
Results: Using computational methods, we identified seven genes (out of 3,592 differentially expressed under chronic hypoxia) that showed correlation with poor prognostic indicators in all three training sets (65/139/73 patients) and this was validated in a fourth data set (91 patients). Retrospectively, the seven-gene set was associated with poor survival (hazard ratio, 1.39; P = 0.007) and early recurrence (hazard ratio, 2.92; P = 0.007) in 135 patients. Moreover, using a hypoxia score based on this seven-gene set, we found that patients with a score of > 0.35 (n = 42) had a median survival of 307 days, whereas patients with a score of = 0.35 (n = 93) had a median survival of 1,602 days (P = 0.005). 
Conclusions: We identified a unique, liver-specific, seven-gene signature associated with chronic hypoxia that correlates with poor prognosis in HCCs.},
  author       = {van Malenstein, Hannah and Gevaert, Olivier and Libbrecht, Louis and Daemen, Anneleen and Allemeersch, Joke and Nevens, Frederik and Van Cutsem, Erik and Cassiman, David and De Moor, Bart and Verslype, Chris and van Pelt, Jos},
  issn         = {1078-0432},
  journal      = {CLINICAL CANCER RESEARCH},
  keywords     = {INTRAHEPATIC RECURRENCE,GENE-EXPRESSION SIGNATURE,THERAPEUTIC TARGETS,COLORECTAL-CANCER,BREAST-CANCER,CLASSIFICATION,CELLS,PREDICTION,SURVIVAL,TUMORS},
  language     = {eng},
  number       = {16},
  pages        = {4278--4288},
  title        = {A seven-gene set associated with chronic hypoxia of prognostic importance in hepatocellular carcinoma},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-09-3274},
  volume       = {16},
  year         = {2010},
}

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